Human insulin (INS) gene diverged from the ancestral genes of invertebrate and mammalian species millions of years ago. We previously found that mouse insulin gene (Ins2) isoforms are expressed in brain choroid plexus (ChP) epithelium cells, where insulin secretion is regulated by serotonin and not by glucose. We further compared human INS isoform expression in postmortem ChP and islets of Langerhans. We uncovered novel INS upstream open reading frame isoforms and their protein products. In addition, we found a novel alternatively spliced isoform that translates to a 74–amino acid (AA) proinsulin containing a shorter 19-AA C-peptide sequence, herein designated Cα-peptide. The middle portion of the conventional C-peptide contains β-sheet (GQVEL) and hairpin (GGGPG) motifs that are not present in Cα-peptide. Islet amyloid polypeptide (IAPP) is not expressed in ChP, and its amyloid formation was inhibited in vitro more efficiently by Cα-peptide than by C-peptide. Of clinical relevance, the ratio of the 74-AA proinsulin to proconvertase-processed Cα-peptide was significantly increased in islets from type 2 diabetes mellitus autopsy donors. Intriguingly, 100 years after the discovery of insulin, we found that INS isoforms are present in ChP from insulin-deficient autopsy donors.

数百万年前，人类胰岛素 ( INS ) 基因从无脊椎动物和哺乳动物的祖先基因中分离出来。我们之前发现小鼠胰岛素基因 ( Ins2 ) 亚型在脑脉络丛 (ChP) 上皮细胞中表达，其中胰岛素分泌受血清素而非葡萄糖调节。我们进一步比较了死后 ChP 和朗格汉斯胰岛中的人类INS亚型表达。我们发现了小说INS上游开放阅读框异构体及其蛋白质产物。此外，我们发现了一种新的可变剪接异构体，它可以转化为包含较短的 19-AA C 肽序列的 74 个氨基酸 (AA) 胰岛素原，本文称为 Cα 肽。常规 C 肽的中间部分包含 Cα 肽中不存在的 β-折叠 (GQVEL) 和发夹 (GGGPG) 基序。胰岛淀粉样多肽 ( IAPP ) 在 ChP 中不表达，Cα 肽在体外比 C 肽更有效地抑制其淀粉样蛋白形成。具有临床意义的是，在 2 型糖尿病尸体解剖供体的胰岛中，74​​-AA 胰岛素原与转化酶原加工的 Cα 肽的比例显着增加。有趣的是，在发现胰岛素 100 年后，我们发现INS异构体存在于来自胰岛素缺乏尸检捐献者的 ChP 中。